EP0541550B1 - Intermédiaires nouveaux, leur préparation et utilisation - Google Patents
Intermédiaires nouveaux, leur préparation et utilisation Download PDFInfo
- Publication number
- EP0541550B1 EP0541550B1 EP90917427A EP90917427A EP0541550B1 EP 0541550 B1 EP0541550 B1 EP 0541550B1 EP 90917427 A EP90917427 A EP 90917427A EP 90917427 A EP90917427 A EP 90917427A EP 0541550 B1 EP0541550 B1 EP 0541550B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- carbonochloridate
- hydrogen
- mmol
- stands
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 *C(OC(*)=O)OC(Cl)=O Chemical compound *C(OC(*)=O)OC(Cl)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to hitherto unknown intermediates of the below formula I for use in the synthesis of prodrugs.
- the said prodrug is non-toxic and, when administered to a warm-blooded animal including a human being, is enzymatically and/or chemically cleaved in such a manner as to release the drug at its target or site of activity, quantitatively and at a desirable rate, while the remaining cleaved moiety remains non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced.
- the prodrug can be provided without excessive costs in connection with its production, in particular without an appreciable loss of drug itself during its production and recovery, since the drug is usually the more expensive part of the prodrug.
- the intermediate used to react with the drug in providing the prodrug should advantageously be stable and still be reasonably reactive.
- acyloxyalkoxycarbonyl derivatives have become interesting bioreversible prodrug moieties of drugs and medicaments which are more readily bioavailable than the drug itself, and further are less irritating to topical and gastric mucosal membranes and are more permeable through such membranes.
- R 1 may be further substituted, and its chain be interrupted by hetero atoms like oxygen, or by carbonyl group(s).
- R 3 means hydrogen or C 1 -C 3 alkyl. Esters of this type have for instance been used as prodrugs of R'COOH and have been shown to be enzymatically hydrolyzed in man. Obviously such esters will also liberate D-H.
- esters of the formula II have been produced in a multi-step procedure, confer J. Med. Chem. 1988, 31, p. 318ff, where the drug (containing a primary or secondary amine group being the point of reaction) is reacted with a compound of formula III in which formula, R 1' and R are hydrogen or lower alkyl.
- the relationship between the reactivities of the two electrophilic centres in (3) is temporarily reversed by conversion of the acid chloride function to the less reactive carbonothioate group of (4).
- the acid chloride function of (7) (being the desired intermediate of formula I) is finally restored by chlorination.
- the double esters (6) were mostly prepared by stirring a suspension of sodium carboxylate in dimethylformamide with the iodo compound (5) at room temperature for 20 hours.
- Simple carboxylic acids tend to give higher yields (80-100%) than carboxylic acids containing additional functional groups.
- Other methods are workable, confer e.g. Scheme A, methods E, F, and J (Examples 9, 10, and 14, respectively).
- the double esters (6) were generally pure enough for subsequent conversion, in step 4 of Scheme A, to the desired intermediates (7) by restoring the acid chloride function through reaction with sulfuryl chloride, preferably in the presence of a catalytic amount of boron trifluoride etherate at -25 - -30 ° C and subsequent stirring at 0 ° C for one hour and half an hour at room temperature.
- the distillable compounds (7) were produced in high yields and could be kept without deterioration for years in a refrigerator.
- the synthetic sequence is not restricted to acyloxymethyl carbonochloridates.
- 1-chloroalkyl carbonochloridates for (3) and treating the derived 0-1-chloroalkyl S-alkyl carbonothioate with TBA butanoate in tetrahydrofuran for a suitable period of time, followed by sulfuryl chloride treatment provided a solution of 1-butanoyloxyalkyl carbonochloridate, but these intermediates seem to be less stable than (7).
- the present intermediates of formula I can generally be prepared by reacting a 1-haloalkyl carbonochloridate of the formula IV where R 3 has the above meanings, is reacted with R 2 SR 4 , R 2 being C 1 -C 4 alkyl, and R 4 being hydrogen or an alkali metal ion, to form a 1-haloalkyl carbonothioate of the formula V R 2 and R 3 having the above meanings, which is transformed into a 1-acyloxyalkyl carbonothioate of the formula VI R 1 , R 2 , and R 3 having the above meanings, by reaction with a salt of a carboxylic acid R 1 COOH, R 1 having the above meanings, and finally reacting the compound of formula VI with a chlorinating agent to yield the desired intermediate of formula I.
- R 3 H
- the present intermediates are preferably being prepared by converting the compound of formula V to the corresponding iodide by reaction with sodium iodide, before transforming it via VI to I.
- the preferred chlorinating agent used in the final step of the preparation of the present intermediates is sulfuryl chloride.
- the present intermediates of the formula I can be provided in good yields and of reasonable costs, that they are stable, and even very reactive, in their intended use in the production of prodrugs. Due to the polyfunctionality of the intermediates, and the known catalytic decomposition of simple alkyl carbonochloridates, acylation reactions like the one used in providing the desired prodrugs could be expected to be troublesome, but this turned out not to be so, as illustrated by the non-optimized reactions of I with a few hydroxyl or amino group containing compounds (Examples 16-21).
- the present intermediates are effective means in the production of the prodrugs in question, and they provide said final prodrugs in good yields in one step processes.
- Example 3 The Procedure of Example 3 is slightly modified by increasing the amount of Nal to 30 g (200 ml), adding NaHCO 3 (0.8 g, 10 mmol), and heating at 40 °C for 4 h. Yield: 23.1 g (94%).
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Claims (8)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB909001405A GB9001405D0 (en) | 1990-01-22 | 1990-01-22 | New intermediates,their production and use |
GB9001405 | 1990-01-22 | ||
PCT/DK1990/000308 WO1991010639A1 (fr) | 1990-01-22 | 1990-11-28 | Nouveaux intermediaires, production et utilisation |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0541550A1 EP0541550A1 (fr) | 1993-05-19 |
EP0541550B1 true EP0541550B1 (fr) | 1994-09-07 |
Family
ID=10669692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90917427A Expired - Lifetime EP0541550B1 (fr) | 1990-01-22 | 1990-11-28 | Intermédiaires nouveaux, leur préparation et utilisation |
Country Status (13)
Country | Link |
---|---|
US (1) | US5401868A (fr) |
EP (1) | EP0541550B1 (fr) |
JP (1) | JP3025532B2 (fr) |
AT (1) | ATE111073T1 (fr) |
AU (1) | AU6883191A (fr) |
CA (1) | CA2064872C (fr) |
DE (1) | DE69012351T2 (fr) |
DK (1) | DK0541550T3 (fr) |
ES (1) | ES2061077T3 (fr) |
GB (1) | GB9001405D0 (fr) |
HU (1) | HUT60459A (fr) |
IE (1) | IE64470B1 (fr) |
WO (1) | WO1991010639A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7790708B2 (en) | 2001-06-11 | 2010-09-07 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20020063837A (ko) | 1999-07-19 | 2002-08-05 | 시오노기세이야쿠가부시키가이샤 | 아실옥시메톡시카르보닐 측쇄를 갖는 삼환 화합물 |
US6376548B1 (en) | 2000-01-28 | 2002-04-23 | Rohm And Haas Company | Enhanced propertied pesticides |
WO2001054481A2 (fr) * | 2000-01-28 | 2001-08-02 | Rohm And Haas Company | Produits pharmaceutiques aux proprietes ameliorees |
US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
KR20040016882A (ko) * | 2001-06-11 | 2004-02-25 | 제노포트 인코포레이티드 | 감소된 독성을 가진 gaba 유사체 프로드러그의 구강투여용 투여 형태물 |
US7232924B2 (en) * | 2001-06-11 | 2007-06-19 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl derivatives of GABA analogs |
WO2003077902A1 (fr) | 2002-02-19 | 2003-09-25 | Xenoport, Inc. | Procede de synthese de promedicaments a partir de derives de 1-acyl-alkyl et compositions correspondantes |
PA8579701A1 (es) * | 2002-08-23 | 2005-05-24 | Pfizer Prod Inc | Profarmaco inhibidor de beta-lactamasa |
BRPI0410936A (pt) * | 2003-06-05 | 2006-06-27 | Pfizer Prod Inc | pró-fármaco inibidor da beta-lactamase |
WO2005010011A2 (fr) * | 2003-07-15 | 2005-02-03 | Xenoport, Inc. | Synthese de composes acyloxyalkyliques |
BRPI0413756A (pt) * | 2003-08-20 | 2006-10-31 | Xenoport Inc | composto, métodos para tratar ou evitar espasticidade ou um sintoma de espasticidade, doença de refluxo gastro-esofágico, vìcio em droga, vìcio em ou abuso de álcool, ou vìcio em ou abuso de nicotina, e tosse ou êmese em um paciente, e, composição farmacêutica |
CN101486668B (zh) * | 2003-12-30 | 2014-07-02 | 什诺波特有限公司 | 酰氧基烃基氨基甲酸酯前药及其中间体的合成 |
EP1716115B1 (fr) * | 2003-12-30 | 2013-02-27 | XenoPort, Inc. | Synthese de promedicaments a base de carbamate d'acyloxyalkyle et leurs intermediaires |
ATE469880T1 (de) | 2005-06-20 | 2010-06-15 | Xenoport Inc | Acyloxyalkylcarbamat-prodrugs von tranexansäure und anwendung |
TW200820963A (en) * | 2006-07-28 | 2008-05-16 | Xenoport Inc | Acyloxyalkyl carbamate prodrugs of α-amino acids, methods of synthesis and use |
TW201014818A (en) * | 2008-06-24 | 2010-04-16 | Teva Pharma | Processes for preparing prodrugs of gabapentin and intermediates thereof |
WO2011028234A1 (fr) * | 2009-09-04 | 2011-03-10 | Xenoport, Inc. | Utilisations de promédicaments acyloxyalkyl carbamates de l'acide tranexamique |
JP6105207B2 (ja) * | 2012-03-30 | 2017-03-29 | 美津濃株式会社 | ラケットフレーム |
US20140024621A1 (en) | 2012-07-23 | 2014-01-23 | Ms Therapeutics Limited | Aminopyridine compounds and their uses |
CN114728883A (zh) * | 2020-08-13 | 2022-07-08 | 南京海融医药科技股份有限公司 | 布洛芬酯类前药、药物组合物以及制备方法和应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3479328A (en) * | 1966-11-18 | 1969-11-18 | Ashland Oil Inc | Novel monomers and polymers |
US3769271A (en) * | 1971-04-15 | 1973-10-30 | Lilly Co Eli | N-protected amino acids and peptides |
FR2363546A1 (fr) * | 1976-09-07 | 1978-03-31 | Poudres & Explosifs Ste Nale | Monomeres mixtes allyliques-acryliques, leur preparation et polymeres en derivant |
DE2939660A1 (de) * | 1979-09-29 | 1981-04-16 | Basf Ag, 6700 Ludwigshafen | Neue carbamate, ihre herstellung und diese enthaltende pharmazeutische zubereitungen |
JPS58189186A (ja) * | 1982-04-30 | 1983-11-04 | Takeda Chem Ind Ltd | セフアロスポリン誘導体 |
IL67445A (en) * | 1982-12-09 | 1985-11-29 | Teva Pharma | Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids |
DE3301670A1 (de) * | 1983-01-20 | 1984-07-26 | Bayer Ag, 5090 Leverkusen | Leimungsmittel |
US5221754A (en) * | 1989-06-09 | 1993-06-22 | Research Corporation Technologies, Inc. | Reagents for rapid peptide synthesis |
-
1990
- 1990-01-22 GB GB909001405A patent/GB9001405D0/en active Pending
- 1990-11-28 AU AU68831/91A patent/AU6883191A/en not_active Abandoned
- 1990-11-28 CA CA002064872A patent/CA2064872C/fr not_active Expired - Fee Related
- 1990-11-28 HU HU9200477A patent/HUT60459A/hu unknown
- 1990-11-28 EP EP90917427A patent/EP0541550B1/fr not_active Expired - Lifetime
- 1990-11-28 DE DE69012351T patent/DE69012351T2/de not_active Expired - Fee Related
- 1990-11-28 AT AT90917427T patent/ATE111073T1/de not_active IP Right Cessation
- 1990-11-28 JP JP3501196A patent/JP3025532B2/ja not_active Expired - Lifetime
- 1990-11-28 DK DK90917427.8T patent/DK0541550T3/da active
- 1990-11-28 WO PCT/DK1990/000308 patent/WO1991010639A1/fr active IP Right Grant
- 1990-11-28 ES ES90917427T patent/ES2061077T3/es not_active Expired - Lifetime
- 1990-11-28 US US07/835,444 patent/US5401868A/en not_active Expired - Lifetime
- 1990-11-29 IE IE430990A patent/IE64470B1/en not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
F.H.C. STEWART: "Formation of Depsipeptide Ester Bonds by Accelerated.......", 1967, Chemistry and Industry, see p. 1960-61, the whole article * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7790708B2 (en) | 2001-06-11 | 2010-09-07 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US8168623B2 (en) | 2001-06-11 | 2012-05-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US8367722B2 (en) | 2001-06-11 | 2013-02-05 | Xenoport, Inc. | Methods of using prodrugs of pregabalin |
US9238616B2 (en) | 2001-06-11 | 2016-01-19 | Xenoport, Inc. | Prodrugs of gaba analogs, compositions and uses thereof |
US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
JPH05503925A (ja) | 1993-06-24 |
DE69012351D1 (de) | 1994-10-13 |
CA2064872C (fr) | 2002-01-22 |
US5401868A (en) | 1995-03-28 |
DE69012351T2 (de) | 1995-02-09 |
CA2064872A1 (fr) | 1991-07-23 |
IE64470B1 (en) | 1995-08-09 |
ES2061077T3 (es) | 1994-12-01 |
HUT60459A (en) | 1992-09-28 |
EP0541550A1 (fr) | 1993-05-19 |
DK0541550T3 (da) | 1994-10-17 |
AU6883191A (en) | 1991-08-05 |
JP3025532B2 (ja) | 2000-03-27 |
HU9200477D0 (en) | 1992-08-28 |
GB9001405D0 (en) | 1990-03-21 |
IE904309A1 (en) | 1991-07-31 |
ATE111073T1 (de) | 1994-09-15 |
WO1991010639A1 (fr) | 1991-07-25 |
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